In the previous grant period, we demonstrated proof of principle that the Hepatocyte Growth Factor (HGF)/c-Met signaling pathway is an important mediator of growth of human non-small cell lung tumors and an independent negative prognostic indicator of poor survival for lung adenocarcinoma patients. We produced three novel inhibitors of the c-Met pathway (an antisense c-Met vector, a competitive inhibitor of HGF, and siRNA to HGF) and also produced a transgenic mouse that overexpresses the HGF gene in the airways and shows enhanced susceptibility to lung carcinogenesis induced by an important tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These results support the validity of targeting the HGF/cMet pathway for therapy and/or prevention of lung cancer. In the proposed second funding period, we will build on those observations with two major goals: understanding more about the mechanism by which the HGF/c-Met pathway increases non-small cell lung cancer (NSCLC) tumor formation and promotes lung tumor growth and progression, and utilizing information about the mechanistic pathways to develop and test anti-tumor agents in preclinical models of human lung cancer. This work will form the rationale for future use of HGF/c-Met-targeted anti-tumor agents in clinical trials. The hypothesis we will test in the next grant period is three-fold (1) The HGF/c-Met pathway activates the enzyme cyclooxygenase 2 (COX-2) via the MAP kinase pathway (and possibly other pathways) in non-small cell lung cancer (NSCLC), resulting in upregulation of important growth-promoting pathways that are controlled by prostaglandins; (2) targeting the HGF/c-Met pathway and the COX-2 pathway alone or together will result in a pronounced reduction in established NSCLC tumor xenograft growth and (3) targeting these pathways also or together will also inhibit or prevent tobacco carcinogen-induced lung tumorigenesis in a transgenic HGF animal model. Three specific aims are proposed to test these hypotheses.